PB2118: TG01-STUDY: A PHASE 1/2 STUDY WITH TG01 IMMUNOTHERAPY VACCINATION IN PATIENTS WITH CONFIRMED NRAS/KRAS MUTATION ON CODON 12/13 AND MULTIPLE MYELOMA OR HIGH-RISK SMOLDERING MYELOMA.
Authors: Hedda Monsen, Hanne Marie Norseth, Nora Remen, Ingerid Abrahamsen, Anna Lysén, Fredik Schjesvold
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: The most prolonged duration of response in multiple myeloma patients (MM) is seen in first-line patients with a deep response. Patients not achieving a deep response following first-line treatment have a worse prognosis and need improved treatment options. Smoldering multiple myeloma (SMM) is not treated until the development of myeloma-defining events. However, analyses of progression from SMM to MM have identified a subpopulation of SMM patients with a significantly increased risk of progression to MM, termed “high-risk SMM” who present with a median time to progression to MM of 2 years. In MM, RAS is the single most mutated gene, and RAS mutations are seen in about 40% of newly diagnosed patients and 50% of relapsed patients. Studies show that NRAS- and KRAS mutations have already been acquired by the diagnosis of SMM, and recent studies suggest that MM is driven by mutations within the RAS signaling cascade. RAS proteins are essential components controlling cellular proliferation, differentiation, and survival. Mutations in HRAS, NRAS, or KRAS genes are among the most common events in human oncogenesis. TG01 is an injectable antigen-specific cancer immunotherapy consisting of 7 different synthetic peptides that mimic fragments of mutant forms of the human RAS protein. More than 150 non-resected and resected pancreatic and colorectal cancer patients have been treated with the peptides that make up TG01. More than 50% of all patients showed immunological responses characterized by positive DTH reaction and T-cell proliferation. Moreover, over 90% of resected pancreatic patients (Study CTN RAS 98010 and CT TG01-01) showed an immunological response. Patients responding immunologically to the RAS peptide treatment appeared to have an increased survival over historical controls. Long-term follow-up of resected pancreatic cancer patients (Study CTN RAS 95002 and 98010) showed a median survival of 27.5 months and 5-year survival of 29% for patients developing immune response after RAS peptide treatment. Aims: We aim to investigate the safety, tolerability, and efficacy of TG01/QS-21 administered as a single agent in patients with MM and high-risk SMM. Methods: Patients with high-risk SMM or MM patients with evidence of measurable disease (per International Myeloma Working Group [IMWG] criteria) following ≥ 1 line of treatment, will be included in this trial to assess whether targeting RAS mutations with TG01 vaccination can provide immunological and clinical responses in these patients.TG01 will be given with QS-21 as an adjuvant. TG01/QS-21 will be administered subcutaneously Q2W for the first 12 weeks, and subsequently at Q2M for a total of 52 weeks or until disease progression. An initial run-in cohort of six patients treated with TG01/QS-21 will be followed by an expansion cohort to include a further 14 patients. The primary endpoint is safety. Patient-reported outcomes and incidence and severity of adverse events will be graded by Common Terminology Criteria for AEs v5.0. Secondary endpoints include Overall Response Rate, Overall Survival, Progression Free Survival, and Time To Next Treatment according to IMWG criteria (2016). As a secondary endpoint we will estimate the size of the RAS mutated clone by next generation sequencing before and after treatment and at the time of progression. Secondary endpoints will also include immunological responses to the vaccine including TG01 T-cell specific cytokine production. We plan for the trial to be open for enrollment in March 2023. Results from this trial will provide insights into a new possible treatment for patients with MM and SMM.Results:Summary/Conclusion: Keywords: Smoldering, Multiple myeloma, Ras